**News Comments** Harvard Lipper Center for Computational Genetics **

These comments on recent articles are intended to clarify recent news stories and support ongoing conversations on these topics. Please join in.

Wanted: Surrogate for Neanderthal Baby (Tech Review, 17-Jan-2013, Susan Young) The first in this series to look like a "want ad". This refers back to a GenomeWeb blurb (earlier on 17-Jan) which refers to a 15-Jan SPIEGEL summary and interview online (both in German and the latter behind a paywall). The English "original" interview came out 18-Jan. On 22-Jan the Boston Herald, Globe and Forbes were the first to note the correct story. On 23-Jan SPIEGEL weighed in on their view of the media distortion -- saying that "The hype machine only got going after we posted the English translation of the interview" (on 18-Jan). But as noted above, hype started on Jan 17. Also note that the English "translation" posted on 18-Jan was not a translation, since the original conversation was in English. They did make a few changes, for example, going from their 7-Jan transcript: "Church: I think so, but, boy, there's a lot of parts to that." to the 18-Jan SPIEGEL Online version: "Church: That depends on a hell of a lot of things, but I think so."
Woman NOT Wanted .. Misquoted Harvard Prof (iMediaEthics, 27-Jan-2013, Sydney Smith)

Geneticist looks for 'how we fit into the universe' (Richmond Times-Dispatch, Mar 2011, Jeff Schapiro) The three mentions of "Human Genome Project" should be "Personal Genome Project". On the point of "parents contacted Church's program" -- actually the Wisconsin geneticists did this without contacting anyone in my group. I cited "HMGC & Children's Hospital of Wisconsin" in my lecture slide. (see Forbes Jan 2011 version). This was fixed online with a few hours.

Geneticist George Church wins Franklin Institute award for genome work (Philadelphia Inquirer, Nov 2010, Faye Flam) The two mentions of the "1000 Genomes Project" should be the "Personal Genome Project". They corrected this online soon after, but later the incorrect early version reappeared.

Mammoth Hemoglobin Offers More Clues to Its Arctic Evolution (NY Times, May 2010, Nicholas Wade) " Dr. Church has been developing a method for altering 50,000 sites at a time" Comment: See Nov 2008 comment below. MAGE (Multiplex Automated Genome Engineering) was published in Nature July 2009. It can handle millions of changes per experiment, but not yet much more than hundreds of precise changes per cell.

George Church creates building block for artificial life (Mass High Tech, Mar 2009, Marc Songini) Marc says that I was "the man who mapped the human genome" and "the founder of the Human Genome Project" and "led the mapping of the human genome". Comment: He did not get those phrases from me. The text that he gave to review for accuracy did not contain any of those lines. I was indeed involved in the first three meetings which conceived the project and in three of the Centers that contributed, but there were at least ten founders and the leaders included Watson, Collins, and the directors of the large sequencing centers. I am also a founder of the Personal Genome Project, but that too is a wonderful team effort, with many leaders.

Regenerating a Mammoth for $10 Million (NY Times, Nov 2008, Nicholas Wade). "a new method Dr. Church has invented for modifying some 50,000 genomic sites at a time". Comment: This is probably a conflation of 1) our new method "MAGE", which we have used to introduce mutations into 50 sites at a time in DNA in bacteria and 2) older methods for introducing a 50,000 bp piece of DNA into one site in a mammalian genome. Manipulation of mammalian DNA cloned in bacteria is often a key step in the process of changing the corresponding DNA in a mammalian cell.

"A wishful-thinking experiment with no realistic chance for success" Comment: The task of making a few key bp changes in the genes regulating hair and tusks of an existing species may be sufficient for a zoo to declare a great success at educating citizens about ancient DNA and to demonstrate the relevance of modern gene replacement methods. At the other extreme, even the replacement of millions of bp in a mammalian genome may also have a chance of success, considering the rapid change in costs of many DNA technologies (e.g. a 10,000 fold improvement in DNA sequencing costs in the past 5 years). When I was a student, many people said that sequencing millions of bp had no realistic chance for success, but now today here we are sequencing many billions of bp.

Google Backs Harvard Scientist's 100,000-Genome Quest. (Bloomberg, Feb 2008, John Lauerman) ; HMS Prof To Expand Genome Database (Crimson, Mar 2008, June Wu). "plans to spend $1 billion" Comment: I'm not sure where they got that number -- possibly multiplying the 100,000 volunteer genomes (mentioned in our latest IRB update) by the X-prize goal of $10K per genome. The PGP goal is closer to $1K (for a partial genome + transcriptome). More importantly, our goal is to make the cost of genomic data and trait data low enough so that large numbers of genetically-literate consumers would have such data anyway and could donate at close to zero cost.

Celebrity genomes alarm researchers (Nature, May 2007, Erika Check) Acknowledging the role wealthy early-adopters play in new technologies and the edutainment value of celebrity, we appreciate Ericka Check's story, yet note the need to clarify the Personal Genome Project stance on elitism and celebrity. We have pursued a 30 year long effort to get the cost of genomics down to an affordable $1000, even sacrificing part of our early role in the genome project, feeling it too expensive ($3 billion) relative to developing technology suitable for average citizens. The PGP was designed in consultation with ethicists to be scaleable (via pre-consent educational tools) to a diverse 100K to million participants, minimizing risk at each stage. The Harvard IRB requested solid knowledge of genetics and risks among the volunteers, which so far consist of educators and stakeholders in public genetics issues (not wealthy celebrities). We ask potential PGP volunteers to consult their families, and this has resulted in exclusion of PGP volunteers. PGP data while obtained with consent to full disclosure, are intended to be initially more secure than feasible with a 'public researcher-only' database, so that subjects can intelligently decide to opt-out before a broad set of researchers (including potentially careless ones) gain access. We are concerned that current practice does not educate subjects about the various means of re-identification from detailed genome/phenome datasets (arep.med.harvard.edu/PGP/Anon.htm). The prospect of a poorly-handled re-identification 'event' strikes us as a potentially larger set-back to genomics than a perceived delay in getting a large set of research subjects.

Reading the Book of Jim. .. pioneering the 'personal genome.' (Newsweek, June 2007, Sharon Begley).
"Genetic variations linked to disease are sprinkled across 0.01 percent of the genome, estimates George Church of Harvard University, who has been pushing technology to make genome sequencing affordable. Those regions could be sequenced for $1,000, he estimates, "and would give you 95 percent of the heavy-hitting mutations"
Comment: While 0.01% is a whopping 300,000 positions and those could cover 95% of the 'heaviest' mutations, the PGP is aiming at 100 times that amount (i.e. a $1K 1% genome) initially and hope to improve on that soon.

Church Hopes to Make DNA Decoding Accessible (Crimson, Aug 2006, Katherine Gray)
"The method he devised is still the most common way people look at three dimensional structures"
Comment: The basic idea had existed already since the mid '60s. Perhaps I was one of the first to make it computational, but that is not important. Another bit of software that I did as part of a team called CORELS has been kept alive now for 30 years by Joel Sussman is arguably more significant. That's a long time for software to survive.

"Their DNA has already been partially sequenced"
Comment: Only two of the ten subjects have been through the consenting and blood-letting (see Globe article below), and only one of those has any polony genome sequencing so far. We have just begun actively recruiting volunteers for the remaining slots. Women in general and men with non-european ancestry are especially encouraged to apply (see PGP).

"An expert examining himself is going to be much more effective"
Comment: An expert examining himself or herself might be more effective for some things, but biased for other things, and generally less effective than a team of experts.
--George

Scan Artist (Boston Globe, Jul 2006, Michael Fitzgerald)
"George and I are co-principal investgiators of the Personal Genome Project [PGP]. George, of course, is an exhibitionist. So what he said is, in the interest of really exploring this issue, he's putting his phenotype, his genotype, and everything on the Web. And I, as co-PI, have said I am also willing to contribute my genotype to research. That was a much more challenging conversation with my wife and daughter. The RFID really has no implications for them other than that my whereabouts could conceivably be tracked. The PGP has a lot of privacy implications."
Comment: John told me that this quote didn't capture his meaning, but even if a bit off-target, it still has value in generating interesting discussion. The HMS IRB requested that I participate in the PGP, and like most of their suggestions this turned out to be very helpful. The PGP is much more 'private' than initially concieved. 'Exhibitionist' has a ring of 'in-your-face behaviorial pathology', while one would hope that the intent of all ten PGP subjects is more a 'willingness to share' (as privately as possible) and to be part of a research team. In a very important sense, PGP is more private than nearly all medical research today, wherein the subjects are kept in the dark, and hence have little basis on which they can decide to opt-out of a project, and conversely no option to shine light on it by making it public either. (See the above Crimson article and also the discussion of problems with current anonymity promises.
--George



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